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1.  The spectrum of nonmotor symptoms in early Parkinson disease 
Neurology  2013;80(3):276-281.
Nonmotor symptoms (NMS) are common in patients with established Parkinson disease (PD) but their frequency in early PD has not been extensively studied. Our aim was to determine the frequency of NMS in a cohort of patients with newly diagnosed PD.
A total of 159 patients with early PD and 99 healthy controls participated in this study. NMS were screened for using the Nonmotor Symptom Questionnaire. Other assessments included measures of motor disability (Movement Disorders Society–revised Unified Parkinson's Disease Rating Scale [MDS-UPDRS]), disease severity (Hoehn & Yahr staging), depression (Geriatric Depression Scale), and global cognitive function (Mini-Mental State Examination and Montreal Cognitive Assessment).
The PD group reported a significantly greater number of NMS compared with controls (8.4 [4.3] vs 2.8 [2.6]). In the PD group, the most commonly experienced NMS were excessive saliva, forgetfulness, urinary urgency, hyposmia, and constipation. Patients with higher MDS-UPDRS III scores and those with the postural instability gait subtype experienced a greater number of NMS.
NMS are common in early PD and reflect the multisystem nature of the disorder. Even in the earliest stages of PD, NMS may be detrimental to patients' functional status and sense of well-being.
PMCID: PMC3589180  PMID: 23319473
2.  Fas Receptor Expression in Germinal-Center B Cells Is Essential for T and B Lymphocyte Homeostasis 
Immunity  2008;29(4):615-627.
Fas is highly expressed in activated and germinal center (GC) B cells but can potentially be inactivated by misguided somatic hypermutation. We employed conditional Fas-deficient mice to investigate the physiological functions of Fas in various B cell subsets. B cell-specific Fas-deficient mice developed fatal lymphoproliferation due to activation of B cells and T cells. Ablation of Fas specifically in GC B cells reproduced the phenotype, indicating that the lymphoproliferation initiates in the GC environment. B cell-specific Fas-deficient mice also showed an accumulation of IgG1+ memory B cells expressing high amounts of CD80 and the expansion of CD28-expressing CD4+ Th cells. Blocking T cell-B cell interaction and GC formation completely prevented the fatal lymphoproliferation. Thus, Fas-mediated selection of GC B cells and the resulting memory B cell compartment is essential for maintaining the homeostasis of both T and B lymphocytes.
PMCID: PMC3470429  PMID: 18835195
3.  The E3 ubiquitin ligase Mule acts through the ATM–p53 axis to maintain B lymphocyte homeostasis 
Genetic manipulation reveals that Mule is vital for B cell development, proliferation, and homeostasis as a result of its ability to regulate p53 and ATM.
Cellular homeostasis is controlled by pathways that balance cell death with survival. Mcl-1 ubiquitin ligase E3 (Mule) is an E3 ubiquitin ligase that targets the proapoptotic molecule p53 for polyubiquitination and degradation. To elucidate the role of Mule in B lymphocyte homeostasis, B cell–specific Mule knockout (BMKO) mice were generated using the Cre–LoxP recombination system. Analysis of BMKO mice showed that Mule was essential for B cell development, proliferation, homeostasis, and humoral immune responses. p53 transactivation was increased by two- to fourfold in Mule-deficient B cells at steady state. Genetic ablation of p53 in BMKO mice restored B cell development, proliferation, and homeostasis. p53 protein was increased in resting Mule-deficient mouse embryonic fibroblasts (MEFs) and embryonic stem (ES) cells. Loss of Mule in both MEFs and B cells at steady state resulted in increased levels of phospho–ataxia telangiectasia mutated (ATM) and the ATM substrate p53. Under genotoxic stress, BMKO B cells were resistant to apoptosis, and control MEFs exhibited evidence of a physical interaction between Mule and phospho-ATM. Phospho-ATM, phospho-p53, and Brca1 levels were reduced in Mule-deficient B cells and MEFs subjected to genotoxic stress. Thus, Mule regulates the ATM–p53 axis to maintain B cell homeostasis under both steady-state and stress conditions.
PMCID: PMC3260869  PMID: 22213803
4.  Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo 
The Journal of Experimental Medicine  2009;206(13):2977-2986.
Nuclear factor interleukin-3 (Nfil3; also known as E4-binding protein 4) is a basic region leucine zipper transcription factor that has antiapoptotic activity in vitro under conditions of growth factor withdrawal. To study the role of Nfil3 in vivo, we generated gene-targeted Nfil3-deficient (Nfil3−/−) mice. Nfil3−/− mice were born at normal Mendelian frequency and were grossly normal and fertile. Although numbers of T cells, B cells, and natural killer (NK) T cells were normal in Nfil3−/− mice, a specific disruption in NK cell development resulted in severely reduced numbers of mature NK cells in the periphery. This defect was NK cell intrinsic in nature, leading to a failure to reject MHC class I–deficient cells in vivo and reductions in both interferon γ production and cytolytic activity in vitro. Our results confirm the specific and essential requirement of Nfil3 for the development of cells of the NK lineage.
PMCID: PMC2806474  PMID: 19995955
5.  CARD6 Is Interferon Inducible but Not Involved in Nucleotide-Binding Oligomerization Domain Protein Signaling Leading to NF-κB Activation▿  
Molecular and Cellular Biology  2007;28(5):1541-1552.
We have previously reported the cloning and characterization of CARD6, a caspase recruitment domain (CARD)-containing protein that is structurally related to the interferon (IFN)-inducible GTPases. CARD6 associates with microtubules and with receptor-interacting protein 2 (RIP2). RIP2 mediates NF-κB activation induced by the intracellular nucleotide-binding oligomerization domain (NOD) receptors that sense bacterial peptidoglycan. Here we report that the expression of CARD6 and RIP2 in bone marrow-derived macrophages is rapidly induced by beta IFN and gamma IFN. This IFN-induced upregulation of CARD6 is suppressed by lipopolysaccharide (LPS), in contrast to LPS's enhancement of IFN-induced RIP2 upregulation. We generated CARD6-deficient (CARD6−/−) mice and carried out extensive analyses of signaling pathways mediating innate and adaptive immune responses, including the NOD pathways, but did not detect any abnormalities. Moreover, CARD6−/− mice were just as susceptible as wild-type mice to infection by Salmonella enterica serovar Typhimurium, Listeria monocytogenes, Candida albicans, lymphocytic choriomeningitis virus, or mouse adenovirus type 1. Thus, although structural and in vitro analyses strongly suggest an important role for CARD6 in immune defense, the physiological function of CARD6 remains obscure.
PMCID: PMC2258768  PMID: 18160713
6.  Generation and Characterization of B7-H4/B7S1/B7x-Deficient Mice 
Molecular and Cellular Biology  2006;26(17):6403-6411.
Members of the B7 family of cosignaling molecules regulate T-cell proliferation and effector functions by engaging cognate receptors on T cells. In vitro and in vivo blockade experiments indicated that B7-H4 (also known as B7S1 or B7x) inhibits proliferation, cytokine production, and cytotoxicity of T cells. B7-H4 binds to an unknown receptor(s) that is expressed on activated T cells. However, whether B7-H4 plays nonredundant immune regulatory roles in vivo has not been tested. We generated B7-H4-deficient mice to investigate the roles of B7-H4 during various immune reactions. Consistent with its inhibitory function in vitro, B7-H4-deficient mice mounted mildly augmented T-helper 1 (Th1) responses and displayed slightly lowered parasite burdens upon Leishmania major infection compared to the wild-type mice. However, the lack of B7-H4 did not affect hypersensitive inflammatory responses in the airway or skin that are induced by either Th1 or Th2 cells. Likewise, B7-H4-deficient mice developed normal cytotoxic T-lymphocyte reactions against viral infection. Thus, B7-H4 plays a negative regulatory role in vivo but the impact of B7-H4 deficiency is minimal. These results suggest that B7-H4 is one of multiple negative cosignaling molecules that collectively provide a fine-tuning mechanism for T-cell-mediated immune responses.
PMCID: PMC1592821  PMID: 16914726
7.  Enhanced TCR-induced Apoptosis in Interferon Regulatory Factor 4–deficient CD4+ Th Cells 
Transcription factors of the interferon regulatory factor (IRF) family contribute to the regulation of cell proliferation and apoptosis. Here, we show that CD4+ T helper (Th) cells lacking IRF4 (IRF4−/−) are highly sensitive to apoptosis. After infection of IRF4−/− mice with the protozoan parasite Leishmania major, the lesion-draining lymph nodes developed the prototypic lymphadenopathy of wild-type mice after 4 wk, but demonstrated almost total loss of cellularity and enhanced apoptosis after 7 wk. In vitro, activation of IRF4−/− CD4+ Th cells led to greatly increased apoptosis compared with wild-type cells. Coculture of IRF4−/− and IRF4+/+ CD4+ cells did not increase survival of IRF4−/− CD4+ cells, indicating that the enhanced rate of IRF4−/− Th cell apoptosis was neither transferable nor due to lack of a cytokine. Enhanced CD4+ cell apoptosis was also observed after anti-CD95 mAb treatment, despite normal CD95 expression. Removal of endogenous cytokines, notably interleukin (IL)-4, led to increased and equally high levels of IRF4−/− and IRF4+/+ cell apoptosis, whereas the protective activity of exogenous IL-4 was reduced in IRF4−/− CD4+ cells despite normal expression of the IL-4 receptor. Therefore, IRF4 is central in protecting CD4+ cells against proapoptotic stimuli.
PMCID: PMC2212018  PMID: 15249594
Th cell; apoptosis; IRF4; CD95; Leishmania major; T helper cell; IL-4
8.  Survivin Loss in Thymocytes Triggers p53-mediated Growth Arrest and p53-independent Cell Death 
Because survivin-null embryos die at an early embryonic stage, the role of survivin in thymocyte development is unknown. We have investigated the role by deleting the survivin gene only in the T lineage and show here that loss of survivin blocks the transition from CD4− CD8− double negative (DN) thymocytes to CD4+ CD8+ double positive cells. Although the pre–T cell receptor signaling pathway is intact in survivin-deficient thymocytes, the cells cannot respond to its signals. In response to proliferative stimuli, cycling survivin-deficient DN cells exhibit cell cycle arrest, a spindle formation defect, and increased cell death. Strikingly, loss of survivin activates the tumor suppressor p53. However, the developmental defects caused by survivin deficiency cannot be rescued by p53 inactivation or introduction of Bcl-2. These lines of evidence indicate that developing thymocytes depend on the cytoprotective function of survivin and that this function is tightly coupled to cell proliferation but independent of p53 and Bcl-2. Thus, survivin plays a critical role in early thymocyte development.
PMCID: PMC2211792  PMID: 14757745
pre–T cell; cell death; development; thymus; mitosis
9.  Chk2 Is a Tumor Suppressor That Regulates Apoptosis in both an Ataxia Telangiectasia Mutated (ATM)-Dependent and an ATM-Independent Manner 
Molecular and Cellular Biology  2002;22(18):6521-6532.
In response to ionizing radiation (IR), the tumor suppressor p53 is stabilized and promotes either cell cycle arrest or apoptosis. Chk2 activated by IR contributes to this stabilization, possibly by direct phosphorylation. Like p53, Chk2 is mutated in patients with Li-Fraumeni syndrome. Since the ataxia telangiectasia mutated (ATM) gene is required for IR-induced activation of Chk2, it has been assumed that ATM and Chk2 act in a linear pathway leading to p53 activation. To clarify the role of Chk2 in tumorigenesis, we generated gene-targeted Chk2-deficient mice. Unlike ATM−/− and p53−/− mice, Chk2−/− mice do not spontaneously develop tumors, although Chk2 does suppress 7,12-dimethylbenzanthracene-induced skin tumors. Tissues from Chk2−/− mice, including those from the thymus, central nervous system, fibroblasts, epidermis, and hair follicles, show significant defects in IR-induced apoptosis or impaired G1/S arrest. Quantitative comparison of the G1/S checkpoint, apoptosis, and expression of p53 proteins in Chk2−/− versus ATM−/− thymocytes suggested that Chk2 can regulate p53-dependent apoptosis in an ATM-independent manner. IR-induced apoptosis was restored in Chk2−/− thymocytes by reintroduction of the wild-type Chk2 gene but not by a Chk2 gene in which the sites phosphorylated by ATM and ataxia telangiectasia and rad3+ related (ATR) were mutated to alanine. ATR may thus selectively contribute to p53-mediated apoptosis. These data indicate that distinct pathways regulate the activation of p53 leading to cell cycle arrest or apoptosis.
PMCID: PMC135625  PMID: 12192050
10.  Generation and Characterization of Smac/DIABLO-Deficient Mice 
Molecular and Cellular Biology  2002;22(10):3509-3517.
The mitochondrial proapoptotic protein Smac/DIABLO has recently been shown to potentiate apoptosis by counteracting the antiapoptotic function of the inhibitor of apoptosis proteins (IAPs). In response to apoptotic stimuli, Smac is released into the cytosol and promotes caspase activation by binding to IAPs, thereby blocking their function. These observations have suggested that Smac is a new regulator of apoptosis. To better understand the physiological function of Smac in normal cells, we generated Smac-deficient (Smac−/−) mice by using homologous recombination in embryonic stem (ES) cells. Smac−/− mice were viable, grew, and matured normally and did not show any histological abnormalities. Although the cleavage in vitro of procaspase-3 was inhibited in lysates of Smac−/− cells, all types of cultured Smac−/− cells tested responded normally to all apoptotic stimuli applied. There were also no detectable differences in Fas-mediated apoptosis in the liver in vivo. Our data strongly suggest the existence of a redundant molecule or molecules capable of compensating for a loss of Smac function.
PMCID: PMC133802  PMID: 11971981
11.  Deficiency in the Transcription Factor Interferon Regulatory Factor (Irf)-2 Leads to Severely Compromised Development of Natural Killer and T Helper Type 1 Cells 
Interferon (IFN) regulatory factor (IRF)-2 was originally described as an antagonist of IRF-1–mediated transcriptional regulation of IFN-inducible genes. IRF-1−/− mice exhibit defective T helper type 1 (Th1) cell differentiation. We have used experimental leishmaniasis to show that, like IRF-1−/− mice, IRF-2−/− mice are susceptible to Leishmania major infection due to a defect in Th1 differentiation. Natural killer (NK) cell development is compromised in both IRF-1−/− and IRF-2−/− mice, but the underlying mechanism differs. NK (but not NK+ T) cell numbers are decreased in IRF-2−/− mice, and the NK cells that are present are immature in phenotype. Therefore, like IRF-1, IRF-2 is required for normal generation of Th1 responses and for NK cell development in vivo. In this particular circumstance the absence of IRF-2 cannot be compensated for by the presence of IRF-1 alone. Mechanistically, IRF-2 may act as a functional agonist rather than antagonist of IRF-1 for some, but not all, IFN-stimulated regulatory element (ISRE)-responsive genes.
PMCID: PMC2193225  PMID: 10934221
interferon regulatory factor; Th1; natural killer cells; Leishmania; interleukin 15
12.  The Transcription Factor Interferon Regulatory Factor 1 (IRF-1) Is Important during the Maturation of Natural Killer 1.1+ T Cell Receptor–α/β+ (NK1+ T) Cells, Natural Killer Cells, and Intestinal Intraepithelial T Cells  
In contrast to conventional T cells, natural killer (NK) 1.1+ T cell receptor (TCR)-α/β+ (NK1+T) cells, NK cells, and intestinal intraepithelial lymphocytes (IELs) bearing CD8-α/α chains constitutively express the interleukin (IL)-2 receptor (R)β/15Rβ chain. Recent studies have indicated that IL-2Rβ/15Rβ chain is required for the development of these lymphocyte subsets, outlining the importance of IL-15. In this study, we investigated the development of these lymphocyte subsets in interferon regulatory factor 1–deficient (IRF-1−/−) mice. Surprisingly, all of these lymphocyte subsets were severely reduced in IRF-1−/− mice. Within CD8-α/α+ intestinal IEL subset, TCR-γ/δ+ cells and TCR-α/β+ cells were equally affected by IRF gene disruption. In contrast to intestinal TCR-γ/δ+ cells, thymic TCR-γ/δ+ cells developed normally in IRF-1−/− mice. Northern blot analysis further revealed that the induction of IL-15 messenger RNA was impaired in IRF-1−/− bone marrow cells, and the recovery of these lymphocyte subsets was observed when IRF-1−/− cells were cultured with IL-15 in vitro. These data indicate that IRF-1 regulates IL-15 gene expression, which may control the development of NK1+T cells, NK cells, and CD8-α/α+ IELs.
PMCID: PMC2212195  PMID: 9500799
13.  Abnormal Development of Intestinal Intraepithelial Lymphocytes and Peripheral Natural Killer Cells in Mice Lacking the IL-2 Receptor β Chain 
The interleukin-2 receptor β chain (IL-2Rβ) is expressed on a variety of hematopoietic cell types, including natural killer (NK) cells and nonconventional T lymphocyte subsets such as intestinal intraepithelial lymphocytes (IEL). However, the importance of IL-2Rβ-mediated signaling in the growth and development of these cells has yet to be clearly established. We have investigated IEL and NK cells in mice deficient for IL-2Rβ and describe here striking defects in the development of these cells. IL-2Rβ−/− mice exhibited an abnormal IEL cell population, characterized by a dramatic reduction in T cell receptor αβ CD8αα and T cell receptor γδ lymphocytes. This selective decrease indicates that IEL can be classified into those whose development and/or differentiation is dependent on IL-2Rβ function and those for which IL-2Rβ–mediated signaling is not essential. NK cell development was also found to be disrupted in IL-2Rβ–deficient mice, characterized by a reduction in NK1.1+CD3− cells in the peripheral circulation and an absence of NK cytotoxic activity in vitro. The dependence of NK cells and certain subclasses of IEL cells on IL-2Rβ expression points to an essential role for signaling through this receptor, presumably by IL-2 and/or IL-15, in the development of lymphocyte subsets of extrathymic origin.
PMCID: PMC2196040  PMID: 9053450

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